Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• R is phenyl-C 2-4 alkenyl unsubstituted or substituted by 1 to 5 C 1-4 alkoxy; benzyl unsubstituted or substituted by amino or diC 1-4 alkylamino; straight-chain or branched C 1-21 alkyl, C 15-21 alkenyl, C 15-21 alkadienyl, C 15-21 alkatrienyl, C 15-21 alkatetraenyl, or C 15-21 alkahexaenyl; retinyl; or C 5-15 carboxyalkyl [Compound of the following formula (1c)]. in which
• the yield is much higher when the above reaction is carried out under cooling rather than under room temperature or warming.
• the above reaction is generally carried out in a solvent which does not adversely affect the reaction.
• a solvent which can be preferably used for this purpose haloalkane solvents, benzene solvents, nitrile solvents, or ether solvents, for example, dichloromethane, dichloroethane, acetone, dioxane, acetonitrile, tetrahydrofuran, etc.
• Particularly preferable solvents among them are haloalkane solvents such as dichloromethane.
• DDPT of formula (3) is esterified in an inert solvent and optionally in the presence of a condensing agent and an organic base with a compound of the following formula (8): R 2 —COOH (8) in which R 2 represents phenyl-C 2-4 alkenyl unsubstituted or substituted by 1 to 5 C 1-4 alkoxy; benzyl unsubstituted or substituted by amino or diC 1-4 alkylamino; straight-chain or branched C 1-21 alkyl, C 15-21 alkenyl, C 15-21 alkadienyl, C 15-21 alkatrienyl, C 15-21 alkatetraenyl, or C 15-21 alkahexaenyl; retinyl; or C 5-15 carboxyalkyl, to give the compound of the following formula (1c) (see Examples 31 to 68): in which R 2 is defined as previously described.
• Example 33 The same procedure as Example 33 was carried out except that 3′-methylbutanoic acid (122 mg, 1.2 mmol) was used to give 412 mg of the title compound.
• Example 33 The same procedure as Example 33 was carried out except that cis-11′-octadecenoic acid (339 mg, 1.2 mmol) was used to give 473 mg of the title compound.
• Example 33 The same procedure as Example 33 was carried out except that sebacic acid (727 mg, 3.6 mmol) was used to give 358 mg of the title compound.
• Example 33 The same procedure as Example 33 was carried out except that tetradecandioic acid (929 mg, 3.6 mmol) was used to give 374 mg of the title compound.
• Cells to be used in the experiment were separated from a surface using 0.5% Trypsin-EDTA solution and suspended in a density of 5 ⁇ 10 4 cell/ml therein.
• the cell suspension was introduced into a 96-well plate in an amount of 180/well and incubated for 24 hours in a 5% CO 2 incubator of 37° C.
• Samples were dissolved in dimethylsulfoxide and then diluted by water distilled in advance for three times just before the experiment. Forty-one (41) samples were prepared into 4 types of final concentrations, i.e., 0.1, 0.03, 0.01 and 0.003 mg per ml of the medium.
• ED 50 values for cancer cells were calculated as follows.
• the amount of SRB protein was analyzed at the time when incubation started by the addition of the sample. This amount was named time zero (Tz).
• the O.D. value obtained from a group which was not treated by the sample was named Control group (C) and the O.D. value obtained from a group which was treated by the sample was named Test group (T).
• mice were bred at a place controlled to the temperature of 23 to 24° C. while provided with water and feed ad libitum. As the feed, feed for mouse containing no antibiotics was used.
• the hypodermic tissue of C57BL/6 mouse which includes cells cultured therein for 14 days, was taken up. Sterilized cold physiological saline was added to the tissue in the amount of 5 ml/g tissue to make a cell suspension. This cell suspension of 0.2 ml was transplanted into the hypodermic region of armpit of BDF1 mouse.
• the compound of formula (1c) was divided into organic acid ester (formula 1c-3 ⁇ 13, 15, 24, 29), unsaturated fatty acid (C-18) ester (formula 1c-16 ⁇ 23), unsaturated fatty acid (C-16, 20 or 22) ester (formula 1c-14, 25 ⁇ 28, 31), and dicarboxylic acid ester (formula 1c-33 ⁇ 38) of DDPT.
• the compound of the present invention generally shows a potent cytotoxicity for A549 and SK-MEL-2 cells.
• the retention time in the blood may be extended.
• cancer cells which grow more rapidly than normal cells may absorb more quickly the essential fatty acid needed for cell growth from the extracellular region. During this process, the cancer cells may selectively absorb the relatively bulky materials having the essential fatty acid.
• the compound of formula (1) according to the present invention exhibits a potent anti-cancer activity. Particularly, it shows a strong cytotoxicity for the cancer cells of A549 and SK-MEL-2, and further a strong inhibition rate against the solid cancer which is induced by the transplantation of LLC cell into the hypodermic region of mouse.
• the compound of the present invention can be prepared by a relatively easy process and has a good solubility, and so can be applied to formulations such as injections with advantage.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 2001
  • 2001-11-19 DE DE60123105T patent/DE60123105T2/de not_active Expired - Fee Related
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